The proposed project uses a cultured myocardial cell system to study both the normal differentiation and induced hypertrophy of myocardial cells. Both processes involve alteration in the expression of specific genes which both reflect, and cause, changes in the differentiation state of the myocardial cell. Little is known about how the intrinsic and extrinsic signals which induce these differentiative changes are transduced to the genes themselves to bring about alteration of their expression. The proposed experiments will address this question in two ways: First, to use DNA-mediated transfer of cloned cardiac-regulated genes into cultured myocardial cells to determine the DNA sequence elements of the genes which respond to; normal differentiative signals, neurotrophic signals, and hypertrophic signals. Second, extrinsic signals (such as norepinephrine) which are known to induce myocardial cell hypertrophy will be investigated as to the cellular mechanism(s) by which they bring about changes in the expression of specific genes, such as cardiac-regulated genes and cellular oncogenes. Finally, the mechanisms by which other putative hypertrophy inducing agents (phorbol esters, thyroid hormone, hydrocortisone) alter myocardial cell gene expression will be investigated to determine if hypertrophy induction operates through many or few intracellular mechanisms. It is expected that this dual approach will facilitate elucidation of the cellular pathways by which both normal and abnormal differentiative signals are transduced to the genes to bring about altered myocardial cell differentiation.